Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region.

Aniridia is an inherited ocular disorder of variable expressivity characterized by iris hypoplasia. A candidate aniridia gene, AN, which is the human homologue of the mouse Pax-6 gene, has recently been isolated by positional cloning from the WAGR region of 11p13. Here we describe mutations in this gene in two cases of sporadic aniridia, one detected at the DNA level and one at the RNA level, both of which are predicted to affect protein function. Mutations in Pax-6 have been described previously in Small eye, the proposed mouse model for aniridia. We present new phenotypic evidence for the validity of this mouse model.

The human PAX6 gene is mutated in two patients with aniridia.

Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age. Complex segregation analysis was performed on these family data. The families were classified into separate categories by extent of aganglionosis. For cases with aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for cases with aganglionosis extending no farther than the sigmoid colon, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance. A model of gene action with random effects during morphogenesis is compatible with our observations.

A genetic study of Hirschsprung disease

Aniridia. A review

Surviving persons from a kindred in which retinoblastoma occurred over four generations, transmitted by eight unaffected individuals, underwent chromosomal analysis. The results revealed that the development of retinoblastoma was associated with a constitutional chromosome deletion del(13)(q13.1q14.5) and that the unaffected transmitting state was associated with a balanced insertional translocation. These findings indicate that predisposition to retinoblastoma may be attributed to the loss of specific genetic material and that a chromosomal mechanism may explain apparent lack of gene penetrance in certain families. The development of unilateral, and not bilateral, retinoblastoma suggests either that the chromosome deletion is different from the mutation of heritable retinoblastoma in general, or that the chromosome deletion lessens the probability of subsequent somatic carcinogenic events.

https://science.sciencemag.org/content/sci/213/4515/1501.full.pdf

Familial retinoblastoma and chromosome 13 deletion transmitted via an insertional translocation

Maximum likelihood analysis for linkage between autosomal dominant aniridia and 12 biochemical and serological markers in a single large family showed a probable linkage between autosomal dominant aniridia and the enzyme acid phosphatase-1. The presence of an autosomal dominant aniridia gene linked to acid phosphatase-1 on chromosome arm 2p and the existence of an aniridia syndrome resulting from deletion of band 13 of the short arm of chromosome 11 establishes a chromosome basis for genetic heterogeneity of aniridia phenotypes.

V. M. Riccardi

Papers

Autosomal dominant aniridia: probable linkage to acid phosphatase-1 locus on chromosome 2

Genetic heterogeneity of aniridia: negative linkage data.